This is a give year competitive renewal to complete genetic studies begun in 1976. The goal has been to gain understanding of the etiology, heterogeneity and comorbidity of major depression (MDD) and its relationship to panic disorder. This last renewal focused efforts on two subtypes of depression (MDD with onset before age 30 and MDD with panic disorder) that our data showed resulted in increased morbidity of MDD in first-degree relatives and specificity in transmission. Over the past four years we have: (1) collected a new sample of 230 probands with early onset MDD, or panic disorder with and without MDD, and normal controls; (2) completed blind interviews with over 700 of their first degree relatives ages 6 and older, and spouses; obtained family history data from multiple informants on over 1,600 first-degree relatives, and collected three or more independent family histories on over 74% of the relatives; (3) identified 17 potentially informative extended pedigrees from the above groups for genetic linkage studies, obtained pedigree data, and conducted interviews with over 176 family members, and (4) established 96 permanent DNA cell lines, and began linkage analyses. In our last year we will complete interviews on another 400 relatives who have consented to be interviewed and will obtain another 50 cell lines. We are requesting funds to (I) conduct data analysis on this new sample of over 1,600 relatives and add it to our existing sample of 1,551 first-degree relatives collected in the same way during the first five years of the grant to determine the heterogeneity, familial patterns, risk and specificity of early onset MDD and of the relationship between MDD and panic disorder through examination of the rates and types of psychiatric disorders in families; to explore genetic models explaining the inheritance of early onset MDD, of panic disorder and the genetic relationship, if any, between panic and MDD; to complete genetic linkage studies using recombinant DNA techniques on the pedigrees already collected, and (II) collect extended pedigrees and establish DNA cell lines in 20 new informative families with panic disorder, with and without depression in order to increase our power to detect linkage, to test a large battery of polymorphic DNA markers against these families and search for locus (loci) that predispose to panic plus MDD or panic. Our preliminary findings suggest this direction may be most fruitful. It is more expedient to target a large number of families with panic disorder at the beginning of gene mapping and not lose momentum or later need to hire and retrain staff. We have collected a large and unique data set and have access to unstudied and potentially informative families that can answer questions about these disorders of relatively high prevalence and social morbidity.